Novel lethal mouse mutants produced in balancer chromosome screens

Hentges, Kathryn E.; Nakamura, Hisashi; Furuta, Yasuhide; Yu, Yuejin; Thompson, Debrah M.; O’Brien, William E.; Bradley, Allan; Justice, Monica J.

doi:10.1016/j.modgep.2005.11.015

Cited by 28 publications

(50 citation statements)

References 56 publications

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“…Nevertheless, because the genes within the inversion are still present, screening for recessive mutations requires the generation of G3 progeny, as described above. Like the deletion screen, balancer screens are also restricted to recovering mutations found within the targeted genomic region [3,4,6,10].…”

Section: Mutant Strain Origins: Spontaneity and Inductionmentioning

confidence: 99%

“…The G2 progeny carrying both the balancer chromosome and the mutagenized chromosome can be identified by coat color and intercrossed, producing only carriers and potential mutants for screening, which are distinguishable by coat color. Progeny receiving two balancer chromosomes may not be viable [3,4,6,10]. The causative mutations underlying several mouse models of peripheral nerve disorder have recently been identified.…”

Section: Future Directionsmentioning

confidence: 99%

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Mouse Forward Genetics in the Study of the Peripheral Nervous System and Human Peripheral Neuropathy

Douglas

Popko

2008

Neurochem Res

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Forward genetics, the phenotype-driven approach to investigating gene identity and function, has a long history in mouse genetics. Random mutations in the mouse transcend bias about gene function and provide avenues towards unique discoveries. The study of the peripheral nervous system is no exception; from historical strains such as the trembler mouse, which led to the identification of PMP22 as a human disease gene causing multiple forms of peripheral neuropathy, to the more recent identification of the claw paw and sprawling mutations, forward genetics has long been a tool for probing the physiology, pathogenesis, and genetics of the PNS. Even as spontaneous and mutagenized mice continue to enable the identification of novel genes, provide allelic series for detailed functional studies, and generate models useful for clinical research, new methods, such as the piggyBac transposon, are being developed to further harness the power of forward genetics.

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Section: Mutant Strain Origins: Spontaneity and Inductionmentioning

confidence: 99%

Section: Future Directionsmentioning

confidence: 99%

Mouse Forward Genetics in the Study of the Peripheral Nervous System and Human Peripheral Neuropathy

Douglas

Popko

2008

Neurochem Res

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“…The results of the ENU screen [11,12] gave insight into the phenotypes we might expect to recover, and importantly, might be rare to discover in a screen. Recessive lethal (63%), neurological (11%), skeletal (6%), and growth/size defects (6%) made up the majority of recovered phenotypes in that study [11].…”

Section: Design Of a Screen To Mutagenize Mouse Chromosome 11mentioning

confidence: 99%

“…Kile et al used the chemical agent N-ethyl-N-nitrosourea (ENU) to mutagenize this Chromosome 11 region of the mouse genome, taking advantage of this engineered chromosome as a ''balancer'' chromosome to facilitate identification of 88 recessive mutations, including lethals, between the Trp53 and Wnt3 loci [11]. Although this approach has uncovered interesting biology in this region of the genome [11,12], associating a single gene disruption with a phenotype has been a challenge due to the lack of a molecular landmark for identifying the ENU-induced mutation. The 88 reported mutations, however, provide an opportunity to evaluate the results of a saturation mutagenesis screen using transposons in the same region of the genome and potentially to assign specific genes to similar phenotypes, because the transposon serves as a molecular tag for mutation.…”

Section: Introductionmentioning

confidence: 99%

“…Here we report the recovery of visible and behavioral mutants, a high rate of recessive lethal phenotypes, and the identification of alternative mechanisms of transposition-mediated mutation. We also compare our experiences to the ENU-based mutagenesis of the same region [11,12] and the aforementioned SB transposoninduced regional mutagenesis of mouse Chromosome 12 [5].…”

Section: Introductionmentioning

confidence: 99%

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Gene mutations and genomic rearrangements in the mouse as a result of transposon mobilization from chromosomal concatemers

Geurts¹,

Collier²,

Geurts³

et al. 2005

PLoS Genet

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Previous studies of the Sleeping Beauty (SB) transposon system, as an insertional mutagen in the germline of mice, have used reverse genetic approaches. These studies have led to its proposed use for regional saturation mutagenesis by taking a forward-genetic approach. Thus, we used the SB system to mutate a region of mouse Chromosome 11 in a forward-genetic screen for recessive lethal and viable phenotypes. This work represents the first reported use of an insertional mutagen in a phenotype-driven approach. The phenotype-driven approach was successful in both recovering visible and behavioral mutants, including dominant limb and recessive behavioral phenotypes, and allowing for the rapid identification of candidate gene disruptions. In addition, a high frequency of recessive lethal mutations arose as a result of genomic rearrangements near the site of transposition, resulting from transposon mobilization. The results suggest that the SB system could be used in a forward-genetic approach to recover interesting phenotypes, but that local chromosomal rearrangements should be anticipated in conjunction with singlecopy, local transposon insertions in chromosomes. Additionally, these mice may serve as a model for chromosome rearrangements caused by transposable elements during the evolution of vertebrate genomes.Citation: Geurts AM, Collier LS, Geurts JL, Oseth LL, Bell ML, et al. (2006) Gene mutations and genomic rearrangements in the mouse as a result of transposon mobilization from chromosomal concatemers. PLoS Genet 2(9): e156.

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A novel hypomorphic Looptail allele at the planar cell polarity Vangl2 gene

et al. 2011

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Vangl2 forms part of the planar cell polarity signalling pathway and is the gene defective in the Looptail (Lp) mouse mutant. Two previously described alleles, Lp and Lpm1Jus, segregate in a semi-dominant fashion, with heterozygotes displaying the looped-tail appearance, while homozygotes show the neural tube defect called craniorachischisis. Here, we report a novel experimentally-induced allele, Lpm2Jus, that carries a missense mutation, R259L, in Vangl2. This mutation was specific to the Lp phenotype and absent from both parental strains and 28 other inbred strains. Notably, this mutation segregates in a recessive manner with all heterozygotes appearing normal and 47% of homozygotes showing a looped-tail. Homozygous Lpm2Jus embryos showed spina bifida in 12%. Lpm2Jus genetically interacts with Lp with 77% of compound heterozygotes displaying craniorachischisis. Vangl2R259L behaved like the wild-type allele in overexpression and morpholino knockdown/rescue assays in zebrafish embryos. These data suggest that Lpm2Jus represents a new hypomorphic allele of Lp.

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Novel lethal mouse mutants produced in balancer chromosome screens

Cited by 28 publications

References 56 publications

Mouse Forward Genetics in the Study of the Peripheral Nervous System and Human Peripheral Neuropathy

Mouse Forward Genetics in the Study of the Peripheral Nervous System and Human Peripheral Neuropathy

Gene mutations and genomic rearrangements in the mouse as a result of transposon mobilization from chromosomal concatemers

A novel hypomorphic Looptail allele at the planar cell polarity Vangl2 gene

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